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类 tolloid 蛋白 1 通过转化生长因子β信号通路负向调控人诱导多能干细胞的肝分化。

Tolloid-Like 1 Negatively Regulates Hepatic Differentiation of Human Induced Pluripotent Stem Cells Through Transforming Growth Factor Beta Signaling.

作者信息

Kiso Ayumi, Toba Yukiko, Tsutsumi Susumu, Deguchi Sayaka, Igai Keisuke, Koshino Saki, Tanaka Yasuhito, Takayama Kazuo, Mizuguchi Hiroyuki

机构信息

Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences Osaka University Osaka Japan.

Laboratory of Hepatocyte Regulation National Institutes of Biomedical Innovation, Health, and Nutrition Osaka Japan.

出版信息

Hepatol Commun. 2020 Jan 2;4(2):255-267. doi: 10.1002/hep4.1466. eCollection 2020 Feb.

DOI:10.1002/hep4.1466
PMID:32025609
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6996343/
Abstract

Single nucleotide polymorphisms in Tolloid-like 1 (TLL1) and the expression of are known to be closely related to hepatocarcinogenesis after hepatitis C virus elimination or liver fibrosis in patients with nonalcoholic fatty liver disease. TLL1 is a type of matrix metalloprotease and has two isoforms in humans, with the short isoform showing higher activity. However, the functional role of TLL1 in human liver development is unknown. Here, we attempted to elucidate the function of human TLL1 using hepatocyte-like cells generated from human pluripotent stem cells. First, we generated TLL1-knockout human induced pluripotent stem (iPS) cells and found that hepatic differentiation was promoted by TLL1 knockout. Next, we explored TLL1-secreting cells using a model of liver development and identified that kinase insert domain receptor (FLK1)-positive cells (mesodermal cells) highly express TLL1. Finally, to elucidate the mechanism by which TLL1 knockout promotes hepatic differentiation, the expression profiles of transforming growth factor beta (), a main target gene of TLL1, and its related genes were analyzed in hepatic differentiation. Both the amount of active TGFβ and the expression of TGFβ target genes were decreased by TLL1 knockout. It is known that TGFβ negatively regulates hepatic differentiation. TLL1 appears to negatively regulate hepatic differentiation of human iPS cells by up-regulating TGFβ signaling. Our findings will provide new insight into the function of TLL1 in human liver development.

摘要

已知类Tolloid 1（TLL1）中的单核苷酸多态性以及[具体基因名称缺失]的表达与丙型肝炎病毒清除后的肝癌发生或非酒精性脂肪性肝病患者的肝纤维化密切相关。TLL1是一种基质金属蛋白酶，在人类中有两种异构体，短异构体显示出更高的活性。然而，TLL1在人类肝脏发育中的功能作用尚不清楚。在这里，我们试图利用从人类多能干细胞生成的肝细胞样细胞来阐明人类TLL1的功能。首先，我们生成了TLL1基因敲除的人类诱导多能干细胞（iPS细胞），发现TLL1基因敲除促进了肝脏分化。接下来，我们使用肝脏发育模型探索分泌TLL1的细胞，并确定激酶插入结构域受体（FLK1）阳性细胞（中胚层细胞）高度表达TLL1。最后，为了阐明TLL1基因敲除促进肝脏分化的机制，我们在肝脏分化过程中分析了TLL1的主要靶基因转化生长因子β（[具体基因名称缺失]）及其相关基因的表达谱。TLL1基因敲除降低了活性TGFβ的量以及TGFβ靶基因的表达。已知TGFβ负向调节肝脏分化。TLL1似乎通过上调TGFβ信号通路负向调节人类iPS细胞的肝脏分化。我们的研究结果将为TLL1在人类肝脏发育中的功能提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/3978a1d64ad7/HEP4-4-255-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/6a2fd1e43ac1/HEP4-4-255-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/0ad92e2a0a15/HEP4-4-255-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/ef2b0cdcbea6/HEP4-4-255-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/f6f472912bf3/HEP4-4-255-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/3978a1d64ad7/HEP4-4-255-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/6a2fd1e43ac1/HEP4-4-255-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/0ad92e2a0a15/HEP4-4-255-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/ef2b0cdcbea6/HEP4-4-255-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/f6f472912bf3/HEP4-4-255-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96c8/6996343/3978a1d64ad7/HEP4-4-255-g005.jpg

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